Does this patient have Sjogren's syndrome?

Sjogren's syndrome (SS) is a chronic inflammatory disorder characterized by dry eyes and dry mouth, driven by pathogenic autoantibodies that target exocrine glands, such as the lacrimal and salivary glands. It can exist on its own (primary SS) or in conjunction with other autoimmune disorders such as rheumatoid arthritis, systemic sclerosis, Hashimoto's thyroiditis, or primary biliary cirrhosis (secondary SS).

Criteria have been developed by a collaborative international group for the classification of primary and secondary SS based on presence of clinical symptoms, autoantibody profile, and histopathological evidence.

The criteria consist of six items:

Ocular symptoms (at least one positive response to the following questions): a) persistent, troublesome dry eyes every day for longer than 3 months, b) recurrent sensation of sand or gravel in the eyes, c) use of a tear substitute more than three times a day.

Oral symptoms (at least one positive response to the following questions): a) feeling of dry mouth every day for at least 3 months, b) recurrent feeling of swollen salivary glands as an adult, c) need to drink liquids to aid in swallowing dry foods.

Objective evidence of ocular involvement (at least one positive result): a) Schirmer's test (less than or equal to 5mm in 5 minutes), b) Rose Bengal score or other ocular dye score (greater than or equal to 4 according to van Bijsterveld scoring system. The scoring system is used to estimate surface damage in sicca and involves placement of 20-25 of a 1% rose Bengal solution in the inferior fornix of both eyes and asking the patient to make 1 or 2 full blinks. The intensity of staining of both the medial and lateral bulbar conjunctiva and of the cornea is scored; the sum of scores for each section (1 - sparsely scattered; 2 - densely scattered, and 3 - confluent) with the maximum score of 9. A score of 4 or more is considered diagnostic of SS.

Histopathology (in minor salivary glands) showing focal lymphocytic sialadenitis, with a focus score greater than or equal to 1, defined as a number of lymphocytic foci per 4mm² of glandular tissue).

Diagnosis of secondary SS requires presence of an associated autoimmune disease and one sicca symptom, in addition to objective evidence of ocular or oral involvement. If no sicca symptoms are present, presence of autoantibodies can be considered.

Patients are usually unaware of ocular dryness, and may complain of excessive tearing or a foreign body-type sensation manifested as a grittiness or sand-like irritation that progresses throughout the day.

Irritation of the eyes, usually bilateral in its involvement, may be accompanied by pain, scratchiness and redness, which may be initially misinterpreted as atopic in etiology.

Other common symptoms include ocular fatigue and blurring of vision due to build-up of thick mucous strands, especially upon awakening.

Chronic dryness of the eyes may result in damage to the cornea, which can lead to pain, photophobia, and discharge, if superimposed infection is present.

Other ocular processes that can mimic KCS include blepharitis, conjunctivitis (viral or bacterial), herpetic keratitis (reactivation or primary infection of the ophthalmic distribution of cranial nerve V), or anterior uveitis (in association with underlying autoimmune condition, often acute in onset and associated with photosensitivity).

Uncommonly, patients may present with an orbital mass, which may be a swollen lacrimal gland. Certain medications (anti-cholinergics) or co-morbid exposures and conditions, such as previous neck radiotherapy, anxiety or depression, must be considered as contributing factors.

Oral symptoms: Dry mouth is a common complaint in SS patients. They describe a parched feeling in their mouth, associated with difficulty eating dry foods (crackers), dysphagia due to adherence of food to buccal surfaces, and changes in taste. Often times, patients report need to supplemental liquids when eating dry foods and ability to speak continuously for prolonged periods due to lack of salivary pool.

Early stages of oral involvement may lack findings of frank oral mucosa dryness, therefore a comprehensive history is critical. In advanced stages, however, signs of absent pooling of saliva in the floor of the mouth as well as increased lobulation and redness of the surface of the tongue (due to depapillation) become evident.

Chronic oral dryness leads to further complications of increased rate of dental caries and periodontal complications, as well as increased rate of intraoral infections (bacterial and candidiasis) due to loss of the protective antibacterial properties of saliva.

Acute onset of pain in the mouth, an unlikely symptom of dry mouth, should stimulate an investigation for signs of intraoral infections or angular cheilitis due to candidiasis.

Early dental loss and formation of caries may be one of the first sign of oral involvement in SS.

Salivary gland symptoms: SS patients may develop swelling of the salivary glands. Most commonly, the parotid glands are involved, but the sublingual as well as the submandibular glands may be affected.

The enlargement of salivary glands, which may start with unilateral and then progress to bilateral involvement, can follow a chronic or episodic pattern of swelling due to the underlying inflammatory process.

Acute pain and tender swelling of the salivary glands, often accompanied by pyrexia and malaise, may indicate the presence of an acute bacterial sialadenitis, usually a staphlyococcal or pneumococcal organism.

Concerns for malignancy should be raised when a hard or nodular gland develops, usually unilateral involvement, along with constitutional symptoms of systemic illness such as weight loss, fever, chills, loss of appetite.

Relative risk of developing lymphoma is 44 times higher in SS patients than age and sex matched controls, usually of B-cell origin, arising from the mucosa associated lymphoid tissue (MALT).

Laboratory and/or serologic predictors have included low C4 levels, appearance of monoclonal proteins or mixed monoclonal cyroglobulinemia, new leukopenia and anemia, or loss of specific autoantibodies. These factors suggest that persistent inflammation is a contributing factor.

Extraglandular manifestations: Systemic, extraglandular involvement in SS can be divided into periepithelial disease, in which lymphocytes invade neighboring tissues producing manifestations such as bronchitis and interstitial nephritis, and extraepithelial disease, which is a result of immune complex deposition resulting in vasculitis and palpable purpura, peripheral neuropathy, and glomerulonephritis. Epithelial involvement include xerosis, Raynaud's phenomenon (which may be associated with vasculitis, arthritis, pulmonary disease, and presence of ANA), and annular eyrthema (usually photosensitive). Other skin lesions may include, and are not limited to, erythema nodosum, livedo reticularis, vitiligo, or lichen planus.

Musculoskeletal involvement includes both joint and muscle manifestations. Joint arthralgias and/or arthritis usually follow a symmetric polyarticular pattern that is non-erosive. Myalgias or mild inflammatory myopathy may also occur in a minority of cases in SS. Significant myopathy with elevated muscle enzymes should raise concern for an overlap connective tissue disorder or myopathic syndromes (polymyositis, inclusion body myositis).

Pulmonary involvement is due to periepithelial lymphocyte invasion and may range from upper airway (due to tracheobronchial sicc symptoms, leading to recurrent non-allergic rhinitis, sinusitis, and dry cough) to parenchymal manifestations (most commonly interstitial lung disease due to lymphocytic pneumonitis, localized mainly in basilar and subpleural regions).

Pericardial involvement is a rare complication in primary SS, which may result in left ventricule hypokinesis.

Renal disease includes tubulointerstitial nephritis affecting the tubules causing renal tubular acidosis, which may also affect the kidney's concentrating ability. Glomerular disease is uncommon, but may occur in primary SS who are positive for antibodies to double-stranded DNA; in these patients; further work-up for amyloidosis, cryoglobulinemia with immune complex deposition, or underlying systemic lupus erythematosus should be done.

Gastrointestinal manifestations mainly include dysphagia due to lack of saliva, but also due to esophageal dysmotility. Endoscopic findings of atrophic gastritis are usually mild in SS but careful examination for Helicobacter pylori is indicated in all patients with gastritis due to its association with MALT (mucosa-associated lymphoid tissue) lymphomas in SS patients.

Thyroid dysfunction, most commonly hypothyroidism, is seen in SS.

Genitourinary manifestations in women commonly include vaginal dryness, which can be associated with dyspareunia.

Neurological involvement is reported in about 20% of patients with SS, most commonly sensory neuropathy affecting cranial and peripheral nerves, and infrequently affecting the central nervous system. Acute onset of tingling or painful dysesthesia in distal limbs signaling mononeuritis multiplex (involving motor and sensory neuropathy) is suggestive of a vasculitic neuropathy due to small or medium-sized vessel inflammation. Nerve biopsy in ischemic neuropathy shows epineural inflammatory infiltrate with axonal degeneration.

Generalized fatigue is one of the more common symptoms affecting approximately 50% of patients with primary SS. Most likely multifactorial in etiology, fatigue can be severe and debilitating, and may be related to subclinical hypothyroidism, psychiatric disorders (depression, anxiety), or fibromyalgia.

The spectrum of clinical manifestations of primary SS may represent an overlap syndrome with features of SLE and scleroderma. The possibility of other disease processes must be continuously re-evaluated during the course of illness especially when findings of keratoconjunctivitis sicca (KCS) and/or dry mouth are not prominent, and when there is a presence of other autoantibodies as well as SS-A and/or SS-B antibodies.

Differentiation of SS from other rheumatic diseases becomes challenging in the initial phases of the disease especially if non-specific manifestations of fatigue, arthralgias, myalgias, Raynaud's phenomenon predominate.

There is a close overlap in symptomatology and autoantibody profile among SS and SLE, as well as RA disease.

What tests to perform?

The diagnostic work-up begins with documenting presence and duration of ocular or oral symptoms that may be present.

Objective tests for ocular involvement (as listed in the diagnostic criteria) include the Schirmer test or rose Bengal test.

The Schirmer test (also known as dry eye test, tearing test, or tear test) quantifies the test formation by placement of filter paper in the lower conjunctival sac, and assessing the length of moisture marked in millimeters (mm) on the filter paper. Normal individuals moisten 15mm of each filter paper, and normal elderly individuals may moisten only 10mm in 5 minutes. SS individuals lack adequate tear production any may moisten less than 5mm in 5 minutes. Anything less than 5mm of moisture on the filter paper is a positive (abnormal) test.

The rose Bengal score is one of the most commonly utilized measures to evaluate ocular surface epithelial damage. It involves placement of 25ml of a 1% rose Bengal solution in the inferior fornix of both eyes and asking the patient to make 1 or 2 full blinks. The intensity of staining of both the medial and lateral bulbar conjunctiva and of the cornea is scored; the sum of scores for each section (1 - sparsely scattered; 2 -densely scattered; 3 - confluent) with the maximum score of 9. A score of 4 or more is considered diagnostic of SS.

Objective assessment of the oral component includes evidence of salivary gland involvement with a minor salivary gland biopsy or test including parotid sialography, salivary scintigraphy, and unstimulated salivary flow measurement.

Parotid sialography provides visualization of the ducts (including a punctate sialadenitis) through retrograde cannulation of the major salivary gland ducts followed by injection of contrast material and X-ray examination. Presence of diffuse sialectasias (punctate, cavitary, or destructive pattern) without evidence of obstruction in major ducts is considered diagnostic of SS.

Sialometry of salivary flow measures unstimulated salivary flow into a calibrated tube for 15 minutes; abnormal flow is defined as less than or equal to 1.5ml in 15 minutes.

Minor salivary gland biopsy is an important criterion for diagnosis of primary SS given its high specificity in experienced hands.

Indications for biopsy include:

Confirmation of suspected clinical diagnosis of SS

Exclusion of other etiologies of xerostomia and bilateral gland enlargement.

A classic finding in SS minor salivary glands is focal lymphocytic sialadenitis, defined as dense infiltration of 50 or more lymphocytes per focus (4mm2) of glandular tissue, based on examination of at least 4 lobules.

Important considerations in interpreting biopsy samples include:

Sample should be taken from normal appearing mucosa and not areas of inflammation to avoid frequent false-positive results. Non-specific sialadenitis with focal infiltrates is commonly found in the normal population.

Pathologic specimen should have adequate number of intact lobules (at least 4), and must discount ruptured lobules.

Exclusion of other conditions that can cause xerostomia and glandular enlargement. SS-like findings, such as parenchymal atrophy and fibrosis with lymphoid cells, have been reported in other connective tissue disorders, chronic infections, and in normal elderly subjects.

Quantitative immunohistology, showing predominance of CD4+ T cells may improve the specificity for SS diagnosis. Expertise in performing and interpreting results of imaging and biopsy samples is critical in increasing the accuracy and specificity of these tests.

Laboratory work-up: A clinical history for persistent, chronic ocular and oral symptoms of dryness associated with systemic features of fatigue or arthralgia should prompt a serologic and laboratory investigation. Aside from the basic survey of the cell count, liver function tests, and basic metabolic profile, autoantibodies including antinuclear antibodies (ANA) and antibodies to extractable nuclear antigens (Ro/SSA, La/SSB) should be checked by either immunodiffusion, enzyme-linked immunosorbent assay (ELISA), or Western blot (depending on which test is available in the laboratory).

Other serologies include rheumatoid factor (RF), complement levels such as complement 3 (C3) and complement 4 (C4), markers of inflammation such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), infectious serologies including HIV, hepatitis C, when indicated to exclude other possible etiologies.

Positive results for ANA might be helpful for diagnosis; however, one must realize that ANA is much more sensitive than it is a specific indicator of SS. The frequency of a positive ANA in the general, healthy population has been quoted as high as 31.7% (titer of 1 to 40) to 3.3% (titer of 1 to 320). Also inter-laboratory variations in the measurement of ANA causes variability in results depending on different techniques (immunoflourescence, ELISA, Western blot) especially when antibody titers are low.

Positive results for anti-Ro/SSA antibodies have been reported in approximately 70 to 97 percent in primary SS. These autoantibodies, directed against cellular proteins with molecular weights of 52-60 kD, can also be found in patients with SLE mainly, but not limited to other connective tissue diseases such as scleroderma, polymyositis, mixed connective tissue disease, and rheumatoid arthritis.

High titers of anti-Ro/SSA antibodies are associated with increased incidence of extraglandular manifestations, such as skin (purpura and cutaneous vasculitis) and nervous system disease.

Presence of anti-Ro/SSA and anti-La/SSB antibodies in pregnant women increases the risk for development of neonatal lupus in the fetus or neonate, and congenital heart block due to placental transfer of these antibodies.

Rheumatoid factor (RF), which are antibodies directed against the Fc portion of IgG, is prevalent in SS patients in up to 75-95 percent.

Interpretation of positive serologies should always occur within the context of the clinical manifestations.

How should patients with Sjogren's syndrome be managed?

Management of SS is directed towards:

The involved visceral and non-visceral organ manifestations

Predominant clinical symptomatology

Treating complications of disease in a timely manner.

Ocular disease

Ophthalmologic consultation is important in the co-management of ocular disease in SS patients.

Targeted therapeutic management for xerophthalmia involves either replacement of moisture (through the use of tear substitutes), preservation of moisture (through ophthalmologic procedures of punctal plugging), and stimulation of moisture (through the use of muscarinic agonist), if refractory to moister preservation or replacement methods.

Moisture preservation methods such as punctal plugging, may involve a temporary (insertion of collagen or silicone plugs) or permanent occlusion (by electrocautery). Patients can also wear specialized protective eye-wear with side chambers to prevent against environmental conditions (i.e. wind) exacerbating ocular dryness. These methods aim to address the discomfort caused by xerostomia, but also to avoid chronic irritation and damage to corneal surface.

Secretagogues, such as pilocarpine hydrochloride and cevimeline hydrochloride, provide stimulation of muscarinic receptors on acinar cells of both lacrimal and salivary glands to promote secretion. Caution must be exercised in patients with co-existing asthma, narrow-angle glaucoma, acute iritis, unstable cardiovascular disease, diarrhea, and other conditions that may worsen with a muscarinic agonist effect.

Oral disease: Treatment of xerostomia should be targeted to alleviate symptoms and also to prevent complications of dental caries and oral infections resulting from chronic xerostomia.

Secretagogues, such as pilocarpine hydrochloride and cevimeline hydrochloride, which stimulate muscarinic receptors, increase salivary gland secretion. Caution must be exercised in patients with co-existing asthma, narrow-angle glaucoma, acute iritis, unstable cardiovascular disease, diarrhea, and other conditions that may worsen with a muscarinic agonist effect.

Stringent, frequent dental care is required in SS patients; consultation with dentists for oral hygiene care and plaque control is recommended at least every 6 months. Infectious complications, such as oral candidiasis, should be suspected in SS patients who develop mouth pain, associated with erythematous or white patches on the mucosal surfaces, and loss of tongue papillae. Treatment for oral candidiasis requires a combination of topical oral preparations (nystatin elixir, miconazole gel). In refractory cases, an alternative preparation is the oral use of nystatin vaginal suppositories (dissolved orally) or amphotericin B lozenges taken with sips of water. Dentures, if applicable, should be disinfected regularly with chlorhexidine solution (0.2 percent) or prevent re-infection.

Clotrimazole or nystatin cream can be used if angular cheilitis is present.

Systemic, non-visceral disease

Pharmacological management for non-visceral manifestations, such as arthralgia, myalgia, and fatigue are generally treated with non-steroidal anti-inflammatory agents (NSAIDs) and hydroxychloroquine (HCQ).

Progressive arthritis consistent with inflammation (with associated swelling, redness, warmth, and dysfunction), may be amenable to corticosteroids, after a stringent exclusion of any infectious etiology or associated connective tissue disease has been done. Corticosteroid use in SS may be effective, but persistent use is limited due to worsening of periodontal disease and oral candidiasis, and the usual long-term side effects such as osteoporosis, glucose intolerance, cardiovascular effects, and mood disturbances. Alternative options for arthralgias also include generic NSAIDs in topical preparations for patients having prominent dysphagia (due to decreased salivary flow).

Hydroxychloroquine (HCQ), an anti-malarial agent, is widely utilized in systemic lupus erythematosus (SLE) for mild systemic manifestations (skin and joint inflammation); HCQ has been shown to have long-term protective effects against lupus flares. Its use in SS patients as in SLE patients has been effective in decreasing arthralgia, myalgia, rash, and lymphadenopathy.

When taken at 6-8 mg/kg daily dose, HCQ has shown good tolerability and safety profile with very rare (probably less than 1 in 1000) occurrences of the classic retinal pigment changes causing maculopathy. Regular ophthalmology examinations (generally every 6-12 months) are recommended to follow the development of eye toxicity.

Systemic, visceral disease

Visceral involvement, including vasculitic skin lesions, nephritis, neuropathy, or interstitial lung disease should be treated with corticosteroids in a similar dosing regimen as used in SLE management.

Steroid-sparing agents, such as HCQ, azathioprine, methotrexate, leflunomide, can be used for further immunosuppression when tapering off corticosteroids.

For life-threatening illness, cyclophosphamide (oral or intravenous) may be required; intravenous therapy is preferred rather than daily oral administration given the high frequency of lymphoma in SS patients.

Emerging therapies targeted against B cells, such as rituximab (anti-CD20 antibody) and epratuzumab (anti-CD22 antibody) are being evaluated.

Data on use for tumor necrosis factor inhibitors, such as infliximab and etanercept, have shown equivocal responses.

What happens to patients with Sjogren's Syndrome?

There are an estimated 2 to 4 million individuals (0.5 to 5% of the population) with SS in the United Sates.

There is a female predominance, with a female to male ratio of 9:1.

Typical onset of disease is in patients in the fourth to sixth decade of their lives, but can occur as early as the second to third decade, or at any age.

Approximately half of all cases of SS are primary; secondary SS is due to other autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis.

Immunopathology

SS is a chronic autoimmune disorder characterized by humoral and cellular activation.

In contrast, B cell levels are increased as evidenced by hypergammaglobulinemia and circulating autoantibodies (SS-A and SS-B) which are present in 75% and 40% in SS patients, respectively.

Approximately two thirds of patients have serum ANA and RF positivity.

Classic histopathologic findings in SS demonstrate focal lymphocytic infiltrates, mainly localized around glandular ducts of the salivary and lacrimal glands, as well as involvement of the respiratory, gastrointestinal, and vaginal tract.

A key part of the diagnostic criteria is a minor salivary gland biopsy demonstrating focal aggregates of at least 50 lymphocytes (predominately CD4+ T cells), plasma cells, and macrophages adjacent to and replacing the normal acini.

Larger foci form structures that resemble germinal centers, in which B cells are autoreactive.

Glandular destruction and dysfunction result as enlargement of the inflammatory foci extends to occupy the acinar epithelium and major salivary glands. These pathologic lesions are classic findings of a chronic lymphocytic sialadenitis.

The initial step in inflammatory cell infiltration occurs at the glandular epithelial cells, which express adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule [ICAM], P and E-selectins) that enhance migration of mononuclear cells to the site of inflammation, up-regulating their antigen presenting function. Cytokines, such as TNF-α and interferon (IFN)-γ also enhance the antigen presenting function of epithelial cells, and in the case of IFN-γ, induce apoptosis of salivary gland epithelial cells, leading to glandular destruction.

Triggers for autoimmunity have been postulated to include environmental pathogens, such as viral infections as a cause primary SS, based on clinical and experimental observations. Viruses, such as Epstein Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), human T-cell lymphotropic virus type-1 (HTLV-1), and hepatitis C virus, can stimulate chronic local, immune responses with findings similar to those of the autoimmune sialadenitis of primary SS. However, causal link between these viruses and disease process is difficult to prove.

Monitoring for lymphoproliferative disease, such as lymphoma, in SS patients is an important task for both internists and rheumatologists.

It has been estimated that SS patients have an approximately 40-fold increased risk of developing non-Hodgkin's lymphoma (NHL) compared to normal age-matched control population.

NHLs associated with SS are predominately B cell in origin, and frequently involve the mucosa associated lymphoid tissue (MALT) near marginal zone, with nodal and extranodal sites including the salivary glands, gastrointestinal tract, lung, skin, thymus, and thyroid gland. Often, these NHLs are indolent but transformation into large cell NHL, a more aggressive form, can occur.

Prognostic factors, such as presence of low complements (C3, C4) and cryoglobulins confer an increased risk (up to 6 to 10-fold) for development of lymphoma.

The presence of these clinical and laboratory features should prompt a deeper investigation of a lymphoproliferative process, including biopsy of lymph node, salivary gland, bone marrow, or imaging studies of head and neck or abdominal region (CT scan).

The mortality rate in primary SS compared to that of the general population is increased in those with these adverse predictors mainly due to development of lymphoproliferative malignancy.

How to utilize team care?

SS is a chronic disease with a wide spectrum of clinical manifestations, and therefore optimal management of SS patients requires a multi-disciplinary approach among all the specialists.

Patients should be followed regularly by their internist or rheumatologist for any significant decline, development of concerning symptoms of malignancy, and signs of disease complications.

Coordination with a team of specialists, including ophthalmologists, dentists, otolaryngologists, and rheumatologists is crucial in the management of this chronic disease.

Treatments that are initially effective may become less effective over time as the disease progresses and/or complications arise.

Artificial tear substitution may be effective initially, however may not be sufficient as tear production become insufficient in which case punctal plugging or use of secretagogues may be indicated.

Frequent monitoring by a dentist, at least twice yearly, for cleaning and flouride therapy is also critical as increased dental caries may be complicated by oral candidiasis.

Systemic features of the disease, such as polyarthralgia, myalgia, fatigue, and more severe features such as vasculitis, glomerulonephritis, or neuropathies require management by a rheumatologist with use of immunosuppressive drugs.

Appropriate referrals and a multi-disciplinary approach are required for care of patients with SS.

Are there clinical practice guidelines to inform decision making?

The diagnostic dilemma in SS is inherent in its indolent course, with initial manifestations that may be mild, and cloud early recognition of the syndrome.

Clinical practical guidelines include:

Identification of the population risk:

Primary SS can occur at all ages and in both sexes, but predominately affects women between ages of 40 and 60 years

Female to male ratio of 9:1.

Focus and defining the clinical manifestations:

Keratoconjunctivitis sicca: due to lacrimal gland involvement leading to diminished tear production involving both corneal and bulbar conjunctival epithelium; patients usually describe constant burning, sandy/gritty sensation under the lids, itchiness, redness, and possibly photophobia.

Xerostomia: due to minor salivary gland involvement leading to decreased saliva production; patients usually describe difficulty eating dry food, dysphagia due to adherence of food to buccal surfaces, changes in taste, inability to speak continuously for prolonged periods, and an increase in dental caries.

Diagnostic work-up tailored by clinical manifestations: Diagnosis of SS is based on an internationally agreed upon set of criteria.

Minor salivary gland biopsy (lip biopsy) is the most common invasive diagnostic procedure; the diagnosis is usually based on relevant history and physical examination with positive serologic evidence.

Serologic testing: anti-Ro and anti-La antibodies are part of the diagnostic criteria, and should be done in all suspected patients. Additional testing for autoantibodies (ANA, RF) can be helpful to evaluate for underlying disorders (SLE or RA) for the diagnosis of secondary SS.